In situ bulking device

ABSTRACT

The present invention relates to a hydrated, biocompatible tissue-augmentation compound and its methodology for implantation into mammalian tissue. The tissue-augmentation compound is comprised of: living tissue, body derived fluids, at least one NCO-terminated hydrophilic urethane prepolymer derived from an organic polyisocyanate, and oxyethylene-based diols or polyols comprised essentially all of hydroxyl groups capped with polyisocyanate

BACKGROUND OF THE INVENTION

1. Field of the invention

The invention relates to methods and substances comprising abiocompatible, non-degradable polymer of stable volume for the purposeof augmenting mammalian tissue.

2. Prior Art

This invention relates to synthetic surgical adhesives/sealants andtissue bulking created by reacting the adhesive tissue augmentationinjectable with living in situ tissue. More specifically, a uniquetissue cross-linked polyurea-urethane bond formed by reaction ofisocyanate capped ethylene oxide diols, triols or polyols with livingtissue forms an immobilized, non-biodegradable augmentation of tissue.

Numerous bulking and plastic surgery applications have been published,but none of them teach bulking by means of the novel substance disclosedhere and further none of them provide adhesion to tissue. Thus in theseprior arts, there is susceptibility to implant migration. The presentinvention is biocompatible. Prior art bulking substances are also knownto be biocompatible, but they are also biodegradable. Biodegradabilityof an implant in a tissue augmentation procedure is generally notdesirable since the benefits conferred by the implanted substancedisappear with time.

U.S. Pat. No. 5,785,642 (Wallace et al.) describes a 3-part injectablepolymer for treating incontinence. While the patent claims improvedresistance to migration, principally when compared with particulateinjectables, it does not describe a tissue bond to guard against implantmigration. Furthermore, the disclosed invention involves forming apolymer precipitate in situ from a solvent/polymer system. Since thesolvent does not entirely become part of the precipitate, then some ofthe injected solvent volume is eventually lost to absorption into thesurrounding tissue. Thus, the invention does not teach a device whichhas a stable volume once implanted.

U.S. Pat. No. 5,712,252 (Smith) describes a method of augmenting softtissue in a mammal, which includes injecting keratin into soft tissue.Keratin is a biodegradable substance.

U.S. Pat. No. 5,763,399 (Lee) describes a composition and method foreffective revitalization of scar tissue by injecting a bioactivesubstance having angiogenic activity. The revitalization of scar tissueis intended to augment existing tissue. However, this invention cannotcontrol the extent of augmentation.

U.S. Pat. No. 5,922,025 (Hubbard) describes a permanent, biocompatiblematerial for soft tissue augmentation. The biocompatible materialcomprises a matrix of smooth, round, finely divided, substantiallyspherical particles of a biocompatible ceramic material. However,prevention of migration of the ceramic material is not described.

U.S. Pat. No. 5,976,526 (Atala) describes treatment of vesicoureteralreflux, incontinence and other defects using an injectable of bladdercells mixed with a liquid polymeric material. This material issusceptible to biodegradation.

U.S. Pat. No. 5,855,615 (Bley at al) describes a composition forinjecting into the urethra comprising a plurality of physiologicallyacceptable solid polymer particles dispersed in a physiologicallyacceptable biodissipatable liquid carrier. The solid polymer particlesare capable of hydrating to a predetermined volume. The injection volumeis therefore not necessarily the same as the final hydrated volume.

U.S. Patent No. 5,709,854 (Griffith-Cima et al) describes a cellpolymeric solution that self-cross-links, but does not bond to tissue,for the purpose of inducing tissue formation.

One of the primary uses of the present invention is treatment or urinaryincontinence. In particular, many women suffer from incontinence causedby childbirth or obesity. The initial treatment for stress incontinenceis exercise to strengthen the pelvic floor muscles. If these exercisesare ineffective, open surgical repair of the bladder neck is oftenattempted. Such surgical repair procedures are not successful for allpatients. There is also risk associated with open surgical procedures,such as trauma, infection, and risks of anesthesia.

As an alternative to surgical repair, urinary incontinence has beentreated by injecting various substances into the tissue surrounding theurethra, i.e., the periurethral tissue, to add bulk to this tissue. Theaim of this treatment is to compress the urethra at the level of thebladder neck to impede involuntary flow of urine from the bladder.

Murless has reported the use of sodium morrhuate for the treatment ofstress incontinence (J. Obstet. Gynaecol., 45:67-71(1938)). Thismaterial was not successful in treating incontinence and pulmonaryinfarction was an observed complication. Paraffin (Acta Urol. Belg.,23:259-262(1955)) and other sclerosing solutions (Urol. Int.,15:225-244(1963)) have been tried yielding poor results.

Polytetrafluoroethylene particles (TEFLON™, POLYTEF™) have been used asinjectable bulking material with a success rate from 30% to 86% in somestudies (J. Urol.,111:180-183(1974); Br.J.Urol.,55:208-210(1983)210(1983); BMJ 228;192 (1984); J .Urol.,(Paris), 62:39-41(1987);Br.J.Urol., 62:39-41 (1988); Aust. N.Z.J.Surg., 61:663-666 (1966)). Thecomplications associated with this procedure were foreign bodygranulomas that tended to migrate to distant organs, such as the lungs,liver, spleen and brain (JAMA, 251:3227-3281 (1984)).

Another injectable used recently is glutaraldehyde cross-linked bovinedermal collagen (Med. J. Aust., 158:89-91 (1993); Br. J. Urol.,75:359-363 (1995); Br.J.Urol., 75: 538-542 (1993)). A major problem withthe use of collagen was biodegradation with associated decrease inimplant volume over time necessitating retreatment (J.Urol., 150:745-747(1993)). Collagen can also cause adverse immune responses and allergicreactions to bovine collagen have been described (Br.J.Urol., 75:359-363(1995)).

Other materials have been suggested for use in the treatment ofvesicourectal reflux. These substances include polyvinyl alcohol foam (J.Urol., 144:531-533 (1990)), glass particles (J.Urol., 148:645 (1992)),a chondrocyte-alginate suspension (J.Urol., 150:745-747 (1993)) and adetachable silicone balloon (J.Urol., 148:724-728 (1992)), each of thesecited journals being incorporated herein by reference.

Injectables have not been suggested for treatment of gastroesophagealreflux disease (GERD), but such use of the disclosed material of thisapplication is envisioned. The material may be injected into the wall ofthe esophagus to thicken the wall and narrow the gastroesophagealjunction into the stomach.

In addition to the need for an immobilized, volume-constant,biocompatible implant, there is also a need to be able to visualize thevolume of injected material during and after implantation. It would bepreferred to monitor the implant size by non-invasive means.Furthermore, fluoroscopic imaging of the implant would aid in estimationof the implant size and location if follow-up injections are necessary.

In addition, polymerization time of the injected material is animportant parameter since the material is typically delivered as a lowviscosity solution that may leak from the site after needle removal. Thelower the viscosity of the injectable the smaller the needle that may beused.

Finally, there are several pragmatic considerations. For example, theinjectable material should not polymerize in the needle of the deliverydevice so as to necessitate replacement of the needle during theprocedure. The solution should be of low viscosity to enable easydelivery of the solution through a 23 G needle.

BRIEF SUMMARY OF THE INVENTION

This invention is directed toward all applications where bulking oftissue provides a functional or aesthetic result. Accordingly, in one ofits method aspects, this invention is directed to a method for treatingurinary incontinence in a mammal, which method comprises delivery of asingle composition comprising a biocompatible prepolymer and a contrastagent to the periurethral tissue of a mammal.

It is an object of the present invention to provide a bulking mass thatchemically bonds in situ to living tissue that is biocompatible,elastomeric, and non-biodegradable.

It is another object of this invention to provide an adhesiveformulation for tissue augmentation surgery having short bonding andpolymerization time.

It is another object of this invention to provide an adhesive bulkingmaterial which is non-toxic and non-immunogenic.

It is another object of this invention to provide a low viscosityadhesive bulking material permitting delivery through a 23 G needle.

It is another object of this invention to provide a bulking materialthat does not undergo appreciable volume change acutely duringpolymerization or chronically after implantation in tissue.

It is another object of this invention that the bulking material providefluoroscopic contrast for noninvasive visualization during and afterimplantation.

It is another object of this invention that the prepolymer compositionbe gamma sterilizable without appreciable cross-linking of theprepolymer or altering its hydrated tissue bond functionality.

The tissue augmentation of this invention is achieved by reacting thetarget tissue with a solution of a high molecular weight ethylene oxidepolyol, triol or diol end-capped with an organic polyisocyanate.

The tissue augmenting agent of this invention may alternatively be apolyisocyanate capped copolymer of ethylene oxide and polypropylene.

The tissue augmenting agent of this invention may additionally contain,in solution, viscosity lowering inert components such as Perfluronbon orphysiologic saline.

It is one primary object of this invention to provide a tissueaugmentation solution that is easily applied, cures quickly in situ, andproduces a strong tissue bond. The preparations disclosed here can bestored at normal hospital room temperatures, and possess long shelflife.

The invention thus comprises a hydrated, biocompatibletissue-augmentation compound comprised of: living tissue, body derivedfluids, at least one NCO-terminated hydrophilic urethane prepolymerderived from an organic polyisocyanate, and oxyethylene-based diols orpolyols comprised essentially all of hydroxyl groups capped withpolyisocyanate. The prepolymer units may preferably be aliphatic oraromatic isocyanate-capped oxyethylene-based diols or polyols. Themolecular weight of the diols or polyols prior to capping withpolyisocyanate is prefarably at least 3,000. The polyisocyanate may be aToluene diisocyanate. The polyisocyanate may be isophorone diisocyanate.The polyisocyanate may be a mixture of Toluene diisocyanate and 6-chloro2,4,5-trifluoro1,3 phenylene diisocyanate. The polyisocyanate may be amixture of Toluene diisocyanate and tetrafluoro1,3-phenylenediisocyanate. The polyisocyanate may be a mixture of diphenylmethanediisocyanate and 6-chloro 2,4,5-trifluoro1,3 phenylene diisocyanate. Thepolyisocyanate may be a mixture of diphenylmethane diisocyanate andtetrafluoro-1,3-phenylene diisocyanate. The polyisocyanate may bepara-phenylene diisocyanate. The diols or polyols may be capped withpolyisocyanate wherein the isocyanate-to-hydroxyl group ratio is between1.5 and 2.5. The isocyanate concentration in the prepolymer units may bebetween 0.05 and 0.8 milliequivalents per gram. The hydrated,biocompatible tissue-augmentation compound may further comprise abiocompatible solvent comprised of acetone to control viscosity and curetime. The hydrated, biocompatible tissue-augmentation compound mayfurther comprise a contrast agent comprised of meglumine. The hydrated,biocompatible tissue-augmentation may further be comprised of a lowmolecular weight uncapped polyethylene glycol, consisting of PEG 300 asa solvent. The hydrated, biocompatible tissue-augmentation compound maybe further comprised of a contrast agent and a biocompatible solvent incombination. The hydrated, biocompatible tissue-augmentation compoundmay be further comprised of physiological saline. The hydrated,biocompatible tissue-augmentation compound may be comprised of between10-30% physiologic saline. The hydrated, biocompatibletissue-augmentation compound may be comprised of 10-20% physiologicsaline. The hydrated, biocompatible tissue-augmentation compound of mayinclude an injectable material selected from the group comprised of:collagen, silicone, teflon, or pyrolytic carbon coated beads.

The invention also includes a method of preparing a crosslinkedhydrophilic, biocompatible hydrated tissue-augmentation compound byreacting together mammalian body tissue, body derived fluids and aprepolymer in a prepolymer-to-water ratio of 3:1 to 20:1, the prepolymerprepared by the steps of: selecting diols or polyols fromoxyethylene-based diols or polyols having an average molecular weight of3,000 to about 30,000, and reacting the diols or polyols with analiphatic or aromatic polyisocyanate at an isocyanate-to-hydroxyl ratioof about 1.5 to 2.5 so that all of the hydroyl groups of said diols orpolyols are capped with polyisocyanate and the resulting prepolymer hasan isocyanate concentration of no more than 0.8 milliequivalents pergram. The diols or polyols may be oxyethylene-based diols or polyols.The diols and polyols of step (a) may be dissolved in an organic solventselected from the group comprising acetonitrile or acetone. The hydratedtissue-augmentation compound may include a solution of non-body derivedwater, including a saline solution containing 0.9% NaCl. Theprepolymer-to-water ratio may be between 3:1 to 20:1. The method mayinclude the step of: washing the bond with a polyfunctional diamine toend isocyanate reactivity.

The invention also includes a prepolymer solution for preparing ahydrophilic, biocompatible tissue augmentation compound characterized byvolume conservation, and resistance to decomposition within the body,said prepolymer consisting of: oxyethylene-based diols or polyols havingan average molecular weight in excess of 3,000, the diols or polyolshaving all of the hydroxyl groups capped with an aromatic or aliphaticdiisocyanate; and an adhesive tissue augmentation injectable having anisocyanate concentration up to 0.8 meq/gm, an addition liquid such asacetone, uncapped PEG, DMSO, or acetone, and a contrast agent such asmeglumine. The prepolymer may include a fluorine containingdiisocyanate. The prepolymer may include a polyfunctional amine such aslysine to end isocyanate reactivity, applied after tissue contact. Theprepolymer may include the step of: heating the compound to atemperature to between about 65-80 degrees C.; and adding the compoundto mammalian body tissue.

The invention also includes a method for treating urinary incontinencein a mammal comprising the steps of: delivering a composition comprisinga biocompatible prepolymer, a biocompatible solvent, and a contrastagent to the periurethral tissue of the mammal wherein said prepolymerreacts with all available water at the site of injection and furtherwherein the delivery results in a polymer matrix of fixed volume formedin situ in the periurethral tissue thereby reducing urinary incontinencein the mammal. The method may include the step of: delivering thecomposition into the periurethral tissue by an endoscopic process, thatis via an endoscope.

The invention also include a method for the delivery of a compositionwhich composition includes a biocompatible prepolymer, a biocompatiblesolvent, and a water soluble contrast agent to the periurethral tissueof a mammal, which tissue already had deposited therein with an initialamount of the composition which method comprises: visualizing theposition of the deposited composition in the periurethral tissue;delivering a prepolymer composition to the periurethral tissue of amammal containing said deposited composition; reacting the biocompatiblepolymer with all available water at the delivery site; and deliveringadditional polymer matrix bonds to the the deposited mass incrementallyto controllably increase the resistance of the flow of urine from thebladder. The method may include the step of: visualizing the depositionof compound by selection of one of the processes of the group consistingof: direct visualization, feel, fluoroscopy or ultrasound.

The invention also includes the method for further treating urinaryincontinence in a mammal, comprising the step of: implanting a firstbiocompatible polymer matrix to a periurethral tissue site of a mammal;implanting a second biocompatible polymer matrix to said site at leastone day after said first implanted biocompatible polymer matrix has beenimplanted at said site, wherein said implanted biocompatible polymermatrix is visualized, and a delivery device is directed to the site, andwherein an additional volume of prepolymer solution is deliveredincrementally to the site, the prepolymer solution bonding to theperiurethral tissue and a previously formed biocompatible polymer mass.

The invention also includes a method for treating GERD in a mammalcomprising the steps of: delivering a composition comprising abiocompatible prepolymer, a biocompatible solvent, and a contrast agentto the gastroesophogeal tissue of the mammal wherein the prepolymerreacts with all available water at the site of injection and furtherwherein the delivery results in a polymer matrix of fixed volume formedin situ in the esophageal tissue thereby reducing GERD in the mammal.The method may include the step of: delivering the composition into thegastroesophageal tissue by an endoscope.

The invention also includes a method for the delivery of a compositionwhich composition includes a biocompatible prepolymer, a biocompatibtesolvent, and a water soluble contrast agent to the gastroesophagealtissue of a mammal, which tissue already had deposited therein with aninitial amount of the deposited composition, which method comprises:visualizing the position of the deposited composition in the esophagealtissue; delivering a prepolymer composition to the esophageal tissue ofa mammal containing the deposited composition; reacting thebiocompatible polymer with all available water at the delivery site; anddelivering additional polymer matrix bonds to the deposited compositionincrementally to controllably increase the resistance of the flow ofgastric juices from the stomach of the mammal. The method may includethe step of: visualizing the deposited composition by selection of oneof the processes of the group consisting of: direct visualization, feel,fluoroscopy or ultrasound.

The invention also includes a method for further treating GERD in amammal, comprising the step of: implanting a first biocompatible polymermatrix to a gastroesophageal tissue site of a mammal; implanting asecond biocompatible polymer matrix to the site at least 24 hours (oneday) after the first implanted biocompatible polymer matrix has beenimplanted at the site, wherein the implanted biocompatible polymermatrix is visualized; and directing a delivery device to the site, andincrementally delivering an additional volume of prepolymer solutionincrementally to the site, the additional volume of prepolymer solutionbonding to esophageal tissue and any previously formed biocompatiblepolymer mass.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to methods for augmenting tissue, andspecifically for treating urinary incontinence and GERD, which methodscomprise delivery of a composition comprising a biocompatibletissue-reactive prepolymer, an inert viscosity lowering medium, and acontrast agent to a tissue site.

The tissue-reactive prepolymer types disclosed here differ from inertpolymers, in that they bond with tissue to form a bulk inert polymer insitu.

The term “biocompatible tissue-reactive prepolymer” refers toprepolymers which, in the amounts employed, are after curing non-toxic,non-peptidyl, non-migratory, chemically inert, and substantiallynon-immunogenic when used internally in a mammal and which aresubstantially insoluble in the periurethral tissue. The bondedbiocompatible polymer does not substantially change volume over time anddoes not migrate to distant organs within the body.

A uniquely flexible, biocompatible, non-biologic tissue bond can beproduced by cross-linking hydrated polymer gels to nitrogenouscomponents found in living tissue. The hydrated tissue augmentation isformed by reacting polymeric monomer units with tissue, at least 75% ofwhich are oxyethylene-based diols or polyols with molecular weightexceeding 10,000. The prepolymer is preferably comprised of hydroxylgroups of diols or polyols substantially all capped by polyisocyanate,where non-polymerized polyisocyanate accounts for less than 4% (v/v) ofthe adhesive tissue augmentation injectable. Amines in the tissue serveto polymerize tissue with the adhesive tissue augmentation injectable.Water mixed or acquired at the bond site generates additional aminethrough reaction with polyisocyanate and serves to polymerize the bulkof the bond.

The addition of an organic liquid lacking an accessible OH, andpreferably one formed in the Krebs cycle can be used to adjust cure timeand prepolymer viscosity. The organic liquid must be completely misciblewith the prepolymer, and essentially polar. When the addition liquid ismiscible it also becomes trapped permanently within the hydrated polymermatrix formed when injected into tissue. Trapping the addition liquid isessential to preserving hydrated polymer matrix volume. Liquids notoccurring naturally within the body may also be used, such as glycerol,but these liquids may not share the same biocompatibility.

The addition of aqueous solution to the prepolymer just beforeapplication represent and embodiment of the present invention, and inthe case of aliphatic prepolymer compositions, typically provide long(>10 minutes) pot life. Where “pot life” is defined as that period oftime just after introduction of the aqueous component to the polyol andjust before gelation sufficient to prevent ejection through thetreatment needle.

Any of the previously known tissue bulking compositions can be combinedwith the present invention. Some of these must be added just prior toinjection, such as any of several animal components, be they autologousor zenologous. In particular, collagen may be used. All of the inertadditives may be added during device packaging, and form the originalingredients of the composition. For example, teflon particles andfibers, pyrolytic carbon coated beads, silicone beads, etc may be addedto the composition. Also, tissue initiators may be added. For example,beta-glucan may be added to promote fibrosis. However, all of the aboveadditions are likely to promote tissue reaction, and therefore must beconsidered less biocompatible.

The diols and polyols used in the tissue bond predominately orexclusively are polyoxyalkylene diols or polyols whose primary buildingblocks are ethylene oxide monomer units. Preferably, 75% of the unitsshould be ethylene oxide. Other adhesive tissue augmentation injectablesystems may contain proportions of propylene oxide or butylene oxideunits in the polyols. The use of these constituents is specificallyavoided in the present invention.

To obtain desirable tissue augmentation injectable viscosity and bondstrength high molecular weight ethylene oxide-based diol and polyols areused to prepare the tissue augmentation injectable. The diol or polyolmolecular weight prior to capping with polyisocyanate should be at least8000 MW, preferably greater than 10,000 MW. Triols (trihydroxycompounds) in the preparation of the polyols are the precursors topreparation of the prepolymer of this invention. There are many suitabletriols: triethanolamine, trimethylolpropane, trimethylolethane, andglycerol. Alternatively, tetrols may be used. Triol- or tetrol-basedpolyols are capped with polyfunctional isocyanate, preferably adiisocyanate.

Alternatively, diols may be used. High molecular weight polyethyleneglycols are satisfactory. Diols are to be end capped with diisocyanatesin addition with cross-linking compounds. Polyfunctional amines andisocyanates are suitable as cross-linking agents. Mixtures of diols andpolyols are also suitable.

The prepolymer of this invention is formed by reacting the hydroxylgroups of the diols or polyols with polyisocyanates. The choice of thepolyisocyanate will depend on factors well known in the art, includingprecursor choice, cure time, and mechanical properties of the tissuebond formed by reacting the prepolymer with tissue.

The choice of precursor is not independent of the choice ofpolyisocyanate. The choice must afford sufficient cross-linking to thetissue so as not to compete detrimentally with internal cross-linkinginitiated with the addition of water to the bond. This competition canbe favorably biased in favor of the tissue bonding reaction by heatingthe tissue augmentation injectable, reducing its viscosity by additionof solvents, or adding macroscopic hygroscopic fillers. The choice mayalso afford rapid bulk polymerization—typically less than 60 seconds.However, in the case of urethral or esophageal bulking a longer pot timeis desired, typically about 15-30 minutes. Increase in bulkpolymerization time can be accomplished by adding acetone or selecting aless reactive polyisocyante.

Aliphatic or cycloaliphatic polyisocyanates are preferred in the aboveembodiments because they result in more biocompatible prepolymers.

Examples of suitable (listed in descending order of suitability)polyfunctional isocyanates are found in the literature, and include thefollowing and commonly obtained mixtures of the following:

9,10-anthracene diisocyanate

1,4-anthracenediisocyanate

benzidine diisocyanate

4,4′-biphenylene diisocyanate

4-bromo-1,3-phenylene diisocyanate

4-chloro-1,3-phenylene diisocyanate

cumene-2,4-diisocyanate

Cyclohexylene-1,2-diisocyanate

Cyclohexylene-1,4-diisocyanate

1,4-cyclohexylene diisocyanate

1,10-decamethylene diisocyanate

3,3′dichloro-4,4′-biphenylene diisocyanate

4,4′diisocyanatodibenzyl

2,4-diisocyanatostilbene

2,6-diisocyanatobenzfuran

2,4-dimethyl1,3-phenylene diisocyanate

5,6-dimethyl1,3-phenylene diisocyanate

4,6-dimethyl1,3-phenylene diisocyanate

3,3′-dimethyl-4,4′diisocyanatodiphenylmethane

2,6-dimethyl-4,4′-diisocyanatodiphenyl

3,3′-dimethoxy-4,4′-diisocyanatodiphenyl

2,4-diisocyantodiphenylether

4,4′-diisocyantodiphenylether

3,3′-diphenyl-4,4′-biphenylene diisocyanate

4,4′-diphenylmethane diisocyanate

4-ethoxy-1,3-phenylene diisocyanate

Ethylene diisocyanate

Ethylidene diisocyanate

2,5-fluorenediisocyanate

1,6-hexamethylene diisocyanate

Isophorone diisocyanate

4-methoxy-1,3-phenylene diisocyanate

methylene dicyclohexyl diisocyanate

m-phenylene diisocyanate

1,5-naphthalene diisocyanate

1,8-naphthalene diisocyanate

polymeric 4,4′-diphenylmethane diisocyanate

p-phenylene diisocyanate

p,p′,p″-triphenylmethane triisocyanate

Propylene-1,2-diisocyanate

p-tetramethyl xylene diisocyanate

1,4-tetramethylene diisocyanate

2,4,6-toluene triisocyanate

trifunctional trimer (isocyanurate) of isophorone diisocyanate

trifunctional biuret of hexamethylene diisocyanate

trifunctional trimer (isocyanurate) of hexamethylene diisocyanate

Bulk curing of the tissue bond of this invention is achieved by usingstoichiometric amounts of reactants. The isocyanate-to-hydroxyl groupratio should be as low as possible without inhibiting bonding function,typically 2+/−10%. Higher ratios achieve adequate bonds but result inexcessive amounts of monomer in the bond. The time period used to capthe polyol or diol is dependent on the polyisocyanate used. Methods forpolyisocyanate capping of polyols are well known.

In forming the tissue augmentation, organic solvents are usefullypresent during the polymerization with tissue to enable a greatertolerance of excessive isocyanate that may disrupt hydrated polymerformation. Varying the amount of solvent also varies the viscosity ofthe tissue augmentation injectable. The porosity of the tissue bond canbe decreased by reducing the viscosity of the prepolymer, andconversely. Useful solvents are ethanol, acetonitrile, saline andacetone.

A prepolymer-aqueous solution may be premixed in ratios up to 1:1 toinitiate polymerization and curing. Alternative, the prepolymer may bedelivered to the site and then followed with an injection ofdifunctional amine to initiate bulk polymerization. Such methods areuseful in obtaining near instantaneous tackiness and fixation.

The prepolymer-to-aqueous solution ratio should be 1:1 to about 20:1,preferably about 5:1 to about 10:1. The ratio is often chosen such thatthe in situ cured mass approximates the surround tissue modulus. Bulkpolymerization time, bond strength and bond porosity increases in thepreferred ratios when the prepolymer content increases.

The implantability of the cured prepolymer of this invention relates tothe bond's ability to present a surface of water to adjacent tissue.When the prepolymers of this invention are used in contact withwater-containing tissues, the ethylene oxide segments of the bondattract and complex with water molecules. Consequently, the surfacepresented to living cells is predominately a layer of water. Theprotective layer of water renders the underlying synthetic polymerictissue bond noninteractive with proteins. Consequently, the curedprepolymer does not remove or denature proteins from the environment inwhich it is implanted.

The prepolymer may also be mixed with a contrast agent or radiopaquematerial. The contrast agent may become part of the polymer matrix asare the water miscible types, or suspended in the polymer matrix as inthe water insoluble type. Water soluble contrast agents includemetrizamide, iopamidol, iothalamate sodium, iodomide sodium, andmeglumine. Examples of water insoluble contrast agents include tantalum,tantalum oxide, gold, tungsten, platinum, and barium sulfate.

The examples that follow are given for illustrative purposes and are notmeant to limit the invention described herein.

EXAMPLE I Preparation of Tissue Augmentation Injectable A

Pluracol V10™ (BASF, propylene oxide/ethylene oxide) is to be deionizedand dried. 2167.3 g deionized Pluracol V10 are to be mixed with 148.5 gisophorone diisocyanate (IPDI) and 0.84 g Santonox R™ (Monsanto ChemicalCo.) and heated at 67 degrees C. under dry nitrogen for 17 days, oruntil isocyanate concentration reaches 0.4 meq/g. The appearance isclear, with a viscosity of 78,000 cps at 22° C. and 1.1 g/ml at 22° C.and free IPDI of approximately 1.5-3% (wt.). The mixture is decanted and100 g of meglumine and 100 g of acetone are mixed until in solution. Theresulting prepolymer will be radiopaque, low viscosity and form ahydrated matrix trapping acetone when mixed with water or injected intoliving tissue.

EXAMPLE II Preparation of Tissue Augmentation Injectable B

Pluracol V10™ (BASF, propylene oxide/ethylene oxide) is to be deionizedand dried. 2170 g deionized Pluracol V10 are to be mixed with 82.4 gIPDI, 150 ml butadione. The mixture is to be heated to 67 degrees C.under dry nitrogen until isocyanate concentration reaches 0.2 meq/g.

EXAMPLE III Preparation of Tissue Augmentation Injectable C

AO-MAL20™ (Shearwater Polymers, Inc., copolymer of M-PEG Allyl Ether andMaleic anhydride) is to be deionized and dried. 900 g deionized TPEG15000 are to be mixed with 45 g IPDI and 0.6 g Santonox R. To thismixture 500 ml acetonitrile is to be added to obtain a liquid. Themixture is to be heated to 72 degrees C. under dry nitrogen untilisocyanate concentration reaches 0.13 meq/g. To this mixture anadditional 100 ml of 0.9% saline is added and 50 g barium sulfate.

EXAMPLE IV Preparation of Tissue Augmentation Injectable D

TPEG1000™ (Union Carbide Corp., polyethylene glycol) is to be deionizedand dried. 1475 g deionized TPEG 10000 are to be mixed with 102.3 g IPDIand 0.79 g Santonox R. The reactants are to be dissolved in 87 mlacetonitrile. The mixture is to be heated to 72 degrees C. under drynitrogen until isocyanate concentration reaches 0.43 meq/g. To thismixture 100 g of dry glycerol are added and mixed.

EXAMPLE V Preparation of Tissue Augmentation Injectable E

BASF#46889 (polyethylene glycol) is to be deionized and dried. 567 gdeionized BASF#46889 are to be mixed with 59 g IPDI and 0.54 g SantonoxR. The reactants are to be dissolved in 572 ml acetonitrile. The mixtureis to be heated to 67 degrees C. under dry nitrogen until isocyanateconcentration reaches 0.46 meq/g.

EXAMPLE VI Preparation of Tissue Augmentation Injectable F

TPEG 10000™ (Union Carbide Corp., polyethylene glycol) is to bedeionized and dried. 475 g deionized TPEG 10000 are to be mixed with102.3 g IPDI and 0.79 g Santonox R. The mixture is to be heated to 72degrees C. under dry nitrogen until isocyanate concentration reaches0.46 meq/g. To this mixture 100 g of acetone are to be added to form aliquid at room temperature.

EXAMPLE VII Preparation of Tissue Augmentation Injectable G

Polyethylene glycol (PEG) (12000 MW) is to be deionized and dried. 0.03moles PEG are to be mixed with 0.15 moles trimethylolpropane and heatedto 60 degrees C. The heated mixture is to be combined, by stirring forone hour, with 0.11 moles commercial isomer blend of xylenediisocyanate. Stirring is to continue until the isocyanate concentrationreaches an asymptote of 0.39 meq/g.

EXAMPLE VIII Preparation of Tissue Augmentation Injectable H

Polyethylene glycol (PEG) (28000 MW) is to be deionized and dried. 0.04moles PEG are to be mixed with 0.2 moles trimethylolpropane and heatedto 60 degrees C. The heated mixture is to be combined, by stirring forone hour, with 0.1 moles commercial isomer blend of xylene diisocyanate.Stirring is to continue until the isocyanate concentration reaches anasymptote of 0.2 meq/g.

EXAMPLE IX Preparation of Tissue Augmentation Injectable I

An adhesive tissue augmentation injectable is to be formed by followingExample I, substituting an equivalent molar amount of commercial isomerblend of Toluene diisocyanate for the IPDI. The isocyanate content is toreach 0.8 meq/g. The appearance should be a light amber liquid of about10,000 cps, containing less than 3.5% free TDI.

EXAMPLE X Preparation of Tissue Augmentation Bond A

Five grams of Adhesive tissue augmentation injectable A are to be mixedwith 1 g water for about 1 minute. The pot time of such a tissueaugmentation injectable mixture is about 1 hr. The mixture is to beapplied to living tissue. The cross-linked structure of tissue andtissue augmentation injectable A are Tissue Bond A.

EXAMPLE XI Preparation of Tissue Augmentation Bond F

Adhesive tissue augmentation injectable G is to be applied directly to atissue surface and mixed at the site with liquid present to reach amixture of 1:5 water-to- tissue augmentation injectable. The cure timeis 30-60 seconds. The cross-linked structure of tissue and Adhesivetissue augmentation injectable G are Tissue Bond F.

EXAMPLE XII Preparation of Tissue Augmentation Bond C

Adhesive tissue augmentation injectable I is to be heated to 65-80degrees C. and applied directly to a tissue surface. The cure time is 30seconds. The cross-linked structure of tissue and Adhesive tissueaugmentation injectable I are Tissue Bond C.

EXAMPLE XIII Preparation of Tissue Augmentation Bond D

The tissue surface is to be swabbed with 3% hydrogen peroxide until thesurface appears white. The treated surface is to be swabbed dry.Adhesive tissue augmentation injectable I is to be heated to 65-80degrees C. and applied directly to a tissue surface. Preferably theadhesive layer on the tissue measures less than 1 mm in thickness. Asecond coat of saturated lysine solution is to be sprayed, but not mixedon the site. Fixing power is achieved immediately. The cross-linkedstructure of activated tissue, Adhesive tissue augmentation injectableI, and lysine are Tissue Bond D.

EXAMPLE XIV Preparation of Tissue Augmentation Bond E

Example XIII if followed except Adhesive tissue augmentation injectableI is premixed with equal volumes of acetonitrile and sprayed on theactivated site. The cross-linked structure is adhesive immediately, butthe acetonitrile is allowed to evaporate to create Tissue Bond E, a thinsealing layer.

The principles, preferred embodiments and modes of operation of thepresent invention have been described in the foregoing specification.The invention that is intended to be protected herein, however, is notto be construed as limited to the particular forms disclosed, sincethese are to be regarded as illustrative rather than restrictive.Variations and changes may be made by those skilled in the art withoutdeparting from the spirit of the invention.

Methods Specific to the treatment of Urinary Incontinence and GERD ofthe present Invention are as follows:

The Tissue Augmentation Prepolymers described above can be employed inmethods for treating urinary incontinence and GERD in mammals. In themethods for treatment of incontinence the composition is injected intothe periurethral tissue via conventional catheter or needle technologyusing, for example, endoscopic or cystoscopic techniques. The injectioncan be accomplished with a puncture needle or spinal needle introduceddirectly or periurethrally with a spinal needle placed percutaneously atthe introitus and positioned in the tissue adjacent to the urethra.Alternatively, the periurethral tissue can be exposed surgically and thecomposition injected directly. Alternatively, the submucosa can beinjected using a William's cystoscopic needle.

Alternatively, the gastroesophageal junction may be bulked by injectioninto the esophageal wall via access inside the esophagus.

Injection of the composition into the target tissue causes thecomposition to gel but not change volume. The formed polymer matrix inthe target tissue maintains the tissue in the swelled state, restrictsthe urethral or esophageal orifice and impedes involuntary flow of urineor gastric juices from the bladder or stomach.

The formed injection does not change shape, and is fully elastic.Collagen and particulate injections can change shape, and consequentlysuffer diminished effectiveness.

The particular amount of composition employed is dictated by the levelof pre-existing support of the target tissue and not dependent upon theconcentration of the prepolymer in the composition or the rate of matrixformation.

The presence of the contrast agent can assist monitoring of the deliverywhile it takes place by fluoroscopy or ultrasound. Monitoring thedelivery of the bulking composition is important to ensure the optimallocation in the target tissue is found and an optimal size of polymermatrix is formed.

The components of the injectable composition intended to aid in deliveryideally do not react with the isocyanate component. Similarly, deliverydevices should not react with the injectable. Polyethylene syringes andstainless steel hypodermic needles are acceptable in the presence of thecomposition described herein. Other materials compatible with thecompositions described here include polyolefins, fluoropolymers, orsilicones.

The methods of this invention are preferably practiced using a kitcontaining a sealed syringe loaded with a prepolymer composition and aneedle of suitable length and gauge. Either the needle produces anopening in the sealed syringe to allow delivery of its contents, or thesyringe is sealed with a removable cap. The cap being one with a LuerLok™ interface with the syringe.

I claim:
 1. A method for treating urinary incontinence in a mammalcomprising the steps of: delivering a composition comprising abiocompatible prepolymer, a biocompatible solvent, and a contrast agentto the periurethral tissue of the mammal wherein said prepolymer reactswith all available water at the site of injection and further whereinsaid delivery results in a polymer matrix of fixed volume formed in situin the periurethral tissue thereby reducing urinary incontinence in themammal.
 2. The method of claim 1 including the step of: delivering saidcomposition into the periurethral tissue by an endoscopic process.
 3. Amethod for treating urinary incontinence in a mammal comprising:injecting a composition of a biocompatable prepolymer, a biocompatablesolvent and a contrast agent to the periurethral tisssue of said mammal;and reacting said prepolymer with all available water at the site ofsaid injection to Form an in situ polymer matrix of fixed volume in theperiurethral tissue of said mammal, thereby resulting in reduced urinaryincontinence in said mamnmal.
 4. The method as recited in claim 3,including: bonding said fixed volume matrix to said periurethral tissueto form a tissue bond thereat.
 5. The method as recited in claim 4,including: delivering said composition into said periurethral tissuethrough an endoscope.
 6. A method for treating urinary incontinence in amammal comprising: injecting a composition of a biocompatableprepolymer, a biocompatable solvent and a contrast agent to theperiurethral tisssue of said mammal; reacting said prepolymer with allavailable water at the site of said injection to form an in situ polymermatrix of fixed volume in the perilrethral tissue of said mammal,thereby resulting in reduced urinary incontinence in said mammal;bonding said fixed volume matrix to said periurethral tissue to form atissue bond thereat; and delivering said composition into saidperiurethral tissue through an endoscope.